This invention relates to the treatment or prevention of depression and/or anxiety by the administration of a combination of a specific class of NK-1 receptor antagonists and an antidepressant or anti-anxiety agent. The present invention also provides preclinical screens for anxiolytic and antidepressant activity of NK-1 receptor antagonists.
Major depression is characterised by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes also occur, especially in severe or xe2x80x9cmelancholicxe2x80x9d depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.
Treatment regimens commonly include the use of tricyclic antidepressants, monoamine oxidase inhibitors, some psychotropic drugs, lithium carbonate, and electroconvulsive therapy (ECT) (see R. J. Baldessarini in Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 19, McGraw-Hill, 1996 for a review). More recently, new classes of antidepressant drugs are being developed including selective serotonin reuptake inhibitors (SSRIs), specific monoamine reuptake inhibitors and 5-HT1A receptor agonists, antagonists and partial agonists.
Anxiety is an emotional condition characterised by feelings such as apprehension and fear accompanied by physical sympoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological.
Anxiety disorders are generally treated using benzodiazepine sedative-antianxiety agents. Potent benzodiazepines are effective in panic disorder as well as in generalised anxiety disorder, however, the risks associated with drug dependency may limit their long-term use. 5-HT1A receptor partial agonists also have useful anxiolytic and other psychotropic activity, and less likelihood of sedation and dependance (see R. J. Baldessarini in Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 18, McGraw-Hill, 1996 for a review).
Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of such conditions include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798).
It might therefore be desirable to investigate the treatment of depression and/or anxiety using a combination of a tachykinin antagonist and an antidepressant and/or an anti-anxiety agent. Indeed, such a desideratum has already been considered in International (PCT) patent specification No. WO 96/24353 (published Aug. 15, 1996) which claims methods for the treatment of psychiatric disorders using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor. However, the disclosure of WO 96/24353 does not provide any teaching as to whether the claimed combination has any efficacy and in particular there is no direction towards specific combinations which might potentiate the antidepressant or anxiolytic effects of the individual therapeutic agents. There is no clear direction from WO 96/24353 to which class of tachykinin antagonist (e.g. NK-1, NK-2 or NK-3 receptor antagonists) would be of use in the claimed combinations, nor how a person of ordinary skill in the art might identify suitable compounds for use in combination with a serotonin agonist or a selective serotonin reuptake inhibitor. Furthermore, there is no teaching which would enable a person of ordinary skill in the art to identify those compounds with sustained activity following oral administration for use in the claimed combinations. At best, WO 96/24353 merely recites in one document that which was already recognised in the art, namely that tachykinin antagonists might be of use in the treatment of psychiatric disorders and that serotonin agonists and selective serotonin reuptake inhibitors are effective in the treatment of psychiatric disorders.
There therefore remains a need for an effective combination of an antidepressant and/or an anti-anxiety agent with a NK-1 receptor antagonist, which combination provides an unexpected and advantageous antidepressant or anxiolytic effect. Such combinations may for example provide an enhanced antidepressant or anxiolytic effect. They may also provide for a rapid onset of action to combat depression and/or anxiety thereby enabling prescription on an xe2x80x9cas-neededxe2x80x9d basis.
CNS-penetrant NK-1 receptor antagonists have been found to provide an unexpected effect relevant to the treatment and prevention of depression and/or anxiety when used in combination with an antidepressant or anti-anxiety agent. While not being bound to any particular theory of operation, an enhanced effect at treating or preventing a psychological stress response in an animal assay is observed with the combination of drugs than would be expected from either drug alone In particular, combination therapy of a CNS-penetrant NK-1 receptor antagonist selected from the compounds of formulae (I), (II), (III), (IV) and (V), and a selective serotonin reuptake inhibitor or a 5-HT1A receptor agonist or antagonist effectively inhibits separation-induced vocalisations in guinea-pig pups. This is indicative of efficacy in the treatment of depression and/or anxiety. Such unexpected results would not have been predicted based on the disclosures in the art.